Effects of drink-stress sequence and gender on alcohol stress response dampening in high and low anxiety sensitive drinkers

BACKGROUND: This study tested the appraisal disruption hypothesis of alcohol stress response dampening (SRD) in male and female high or low anxiety sensitive (AS) undergraduates. The hypothesis predicts that alcohol SRD will be greater when drinking occurs before versus after stress exposure. High AS males' predominant social-evaluative concerns further implied that alcohol SRD to a social stressor (i.e., a speech) would be relatively stronger in high AS males than in high AS females. METHODS: Male and female (n=90/gender) high and low AS participants (>or=70th; 相似文献   

Alcohol effects on cerebral blood flow in subjects with low and high responses to alcohol

Background: Although there are multiple indications that alcohol can alter many physiological brain functions, including cerebral blood flow (CBF), studies of the latter have generally used small‐ or modest‐sized samples. Few investigations have yet evaluated how CBF changes after alcohol relate to subsets of subjects with elevated alcoholism risks, such as those with lower levels of response (LR) to alcohol. This study used arterial spin labeling (ASL) after alcohol administration to evaluate a large sample of healthy young men and women with low and high alcohol responses, and, thus, varying risks for alcohol use disorders (AUD). Methods: Healthy young adult social drinkers with low and high LR (N = 88, 50% women) matched on demography and drinking histories were imaged with whole‐brain resting ASL ～1 hour after ingesting ～3 drinks of ethanol and after a placebo beverage (i.e., 178 ASL sessions). The relationships of CBF changes from placebo to alcohol for subjects with low and high LR were evaluated. Results: CBF increased after alcohol when compared to placebo in 5 frontal brain regions. Despite identical blood alcohol concentrations, these increases with alcohol were less prominent in individuals who required more drinks to experience alcohol‐related effects (i.e., had a lower LR to alcohol). The LR group differences remained significant after covarying for recent drinking quantities. Conclusions: The results confirm that alcohol intake is associated with acute increases in CBF, particularly in frontal regions. Less intense CBF changes were seen in subjects with a genetically influenced characteristic, a low LR to alcohol, that relates to the future risk of heavy drinking and alcohol problems.     

Autosomal linkage analysis for the level of response to alcohol

BACKGROUND: The level of response (LR) to alcohol is a genetically-influenced phenotype related to the alcoholism risk. Usually measured by evaluating psychological and physiological changes that follow the administration of alcohol, the heritability of LR is estimated to be between 0.4 and 0.6, and efforts are being made to find genes related to this phenotype. This paper presents data from a family-based genome with linkage analysis focusing on alcohol challenge determinants of LR. METHODS: The subjects were 18-to-29-year-old sibling pairs with at least one parent who was alcohol-dependent and who had experience with alcohol but were not yet alcohol-dependent themselves. Both members of the sibling pairs were given oral alcohol challenges (0.75-0.90 ml/kg of ethanol for females and males, respectively), with LR established using the Subjective High Assessment Scale (SHAS) and changes in body sway (BS) repeatedly over a 3.5-hr. period. Blood samples from siblings and at least one parent were genotyped using 811 microsatellite markers, with results evaluated using several related variance component approaches as implemented in SOLAR for continuous traits. In addition, association was tested using single nucleotide polymorphisms (SNPs) within the KCNMA1, HTR7 and SLC18A2 genes that may relate to a finding on chromosome 10. RESULTS: Data were generated from 238 sib-pairs representing 365 individuals (41.6% were males) from 165 families. The most consistent results across methods and samples were observed for SHAS on chromosome 10 between 120 and 140 cM (with a maximum LOD score of 2.6 at 122 cM), and a second region of possible interest at 173 cM (LOD = 1.2). Statistical analysis with the KCNMA1, HTR7 and SLC18A2 genes, which lie in the support region of interest revealed no evidence for association after correction for multiple comparisons. CONCLUSIONS: These evaluations from the largest known alcohol challenge-based genetic study to date highlight the potential importance of genes on chromosome 10 as possible contributors to the low LR to alcohol as a risk factor for alcoholism.     

Biphasic alcohol response differs in heavy versus light drinkers

BACKGROUND: Most studies of risk factors for alcohol-related problems have focused on biological family history as a primary risk factor. However, other factors, such as early-age heavy drinking, are also risk factors for sustained or progressive heavy consumption. Little is currently known about the mechanisms underlying binge or heavy drinking. METHODS: This study examined the acute subjective and objective effects of ethanol in heavy drinkers versus light drinkers. Thirty-four subjects participated in this within-subjects study consisting of three early-evening testing sessions in which subjects consumed a beverage containing either 0.8 or 0.4 g/kg ethanol or placebo. RESULTS: Compared with lighter drinkers, heavy drinkers were more sensitive to the positive stimulant-like effects of ethanol (p < 0.05), especially during the increasing limb of the blood alcohol curve. Heavy drinkers also showed less sedation and cortisol response after alcohol than the light drinkers (p < 0.05). CONCLUSIONS: The results indicate that young adult binge drinkers show a biphasic alcohol response, with heightened sensitivity to stimulant-like alcohol effects and greater tolerance to sedative alcohol effects compared with their light-drinking counterparts.     

The search for genes contributing to the low level of response to alcohol: patterns of findings across studies

BACKGROUND: Alcoholism is a complex genetically influenced disorder in which multiple phenotypes [e.g., disinhibition, alcohol-metabolizing patterns, and the low level of response (LR) to alcohol] contribute to the risk. A low LR to alcohol is one of the more thoroughly studied risk phenotypes; data indicate that LR relates to the risk status, predicts future alcoholism, and has a heritability as high as 60%. This article reviews data from animal and human studies regarding the LR to alcohol, searching for a convergence of results that might lead to the identification of relevant genes. METHODS: A literature search was performed regarding animal and human genetic studies focusing on genes that might affect the LR to alcohol as a risk factor for alcoholism. The goal was to synthesize these results and highlight potential patterns. RESULTS: Focusing on both genetic linkage and association studies, a number of chromosomal regions and genes potentially relevant to findings across two or more sources were identified. The genes of potential interest fell into several categories, including second-messenger systems (e.g., G proteins, adenylyl cyclase, and protein kinases); neurotransmitters or drug-related receptors (e.g., gamma-aminobutyric acid-A, glutamate, serotonin, and cannabinoid and opioid receptors); genes that affect alcohol metabolism; and genes that might relate to an overlap in the risk for alcoholism and some psychiatric conditions (e.g., catechol-O-methyltransferase regarding schizophrenia and bipolar disorder). CONCLUSIONS: The review identifies several genes that may contribute to a low LR to alcohol and, thus, to an increased risk for alcohol use disorders. The chromosomal regions and genes highlighted here may form the basis for more focused genetic studies of alcohol use disorders, with the goals of developing more specific and effective prevention and treatment approaches.     

Integrative neurobiology of the alcohol withdrawal syndrome--from anxiety to seizures

This article represents the proceedings of a symposium presented at the 2003 Research Society on Alcoholism meeting in Ft. Lauderdale, Florida, organized and chaired by Carl L. Faingold. The presentations were (1) Overview, by Carl L. Faingold; (2) Stress, Multiple Alcohol Withdrawals, and Anxiety, by Darin Knapp; (3) Relationship Between Genetic Differences in Alcohol Drinking and Alcohol Withdrawal, by Julia Chester; (4) Neuronal Mechanisms in the Network for Alcohol Withdrawal Seizures: Modulation by Excitatory Amino Acid Receptors, by Carl L. Faingold; and (5) Treatment of Acute Alcohol Withdrawal and Long-Lasting Alterations in Hippocampal Neuronal Networks, by Larry P. Gonzalez. The presentations emphasized the importance of using intact behaving animals to advance the understanding of the human alcohol withdrawal syndrome. This involves applying and amplifying the neurophysiological and neurotransmitter findings observed in vitro to the network-based neurobiological mechanisms that are involved in several important aspects of the specific behaviors observed clinically. The symposium provided evidence that the organizational aspects of neuronal networks in the intact nervous system add another nexus for the action of alcohol and drugs to treat alcohol withdrawal that may not be readily studied in isolated neural elements used in in vitro approaches.     

fMRI differences between subjects with low and high responses to alcohol during a stop signal task

Background: A low level of response (i.e., a low LR) to alcohol is a genetically influenced phenotype that predicts later alcoholism. While the low LR reflects, at least in part, a low brain response to alcohol, the physiological underpinnings of the low LR have only recently been addressed. Methods: Forty‐nine drinking but not yet alcoholic matched pairs of 18‐ to 25‐year‐old subjects (N = 98; 53% women) with low and high LRs as established in separate alcohol challenges were evaluated in 2 event‐related functional magnetic resonance imaging (fMRI) sessions (placebo and approximately 0.7 ml/kg of alcohol) while performing a validated stop signal task. The high and low LR groups had identical blood alcohol levels during the alcohol session. Results: Significant high versus low LR group and LR group × condition effects were observed in blood oxygen level–dependent (BOLD) signal during error and inhibitory processing, despite similar LR group performance on the task. In most clusters with significant (corrected p < 0.05, clusters > 1,344 μl) LR group × alcohol/placebo condition interactions, the low LR group demonstrated relatively less, whereas the high LR group demonstrated more, error and inhibition‐related activation after alcohol compared with placebo. Conclusions: This is one of the first fMRI studies to demonstrate significant differences between healthy groups with different risks of a future life‐threatening disorder. The results may suggest a brain mechanism that contributes to how a low LR might enhance the risk of future heavy drinking and alcohol dependence.     

Reduced adrenal activation in a rat line selected for high alcohol sensitivity

BACKGROUND: A rat line developed by selective breeding for high alcohol sensitivity has blunted corticosterone responses to alcohol and stress. In the present study, we determined possible differences in adrenal activation after alcohol and motor performance testing between the alcohol-sensitive alcohol-nontolerant and alcohol-insensitive alcohol-tolerant rats. METHODS: The animals received ethanol (2 g/kg, intraperitoneally), and 30 min later they were subjected to a motor function test (i.e., normal selection test used in the breeding of the lines); the control animals for both rat lines received no treatment and minimal handling. Blood corticosterone and ACTH levels at the single time point were determined by radioimmunoassay, and adrenal activation was determined by in situ hybridization of the immediate early gene c-fos, nor1, nurr1, and NGFI-B mRNA expression. RESULTS: The alcohol nontolerant rats had lower corticosterone but normal ACTH levels after ethanol and motor testing. Adrenal early gene expression of all of the genes studied was strongly induced by the treatment in both rat lines, but the inductions of c-fos, nor1, and nurr1 were significantly lower in the alcohol-sensitive animals. Acute treatment with a high dose of ACTH also induced less adrenal gene expression in the alcohol-sensitive animals. CONCLUSIONS: The results suggest that the reduced adrenal activation is associated with high alcohol sensitivity in a genetic animal model, which is in agreement with the human findings of alcohol insensitivity during glucocorticoid treatment.     

Relationships among the level of response to alcohol and the number of alcoholic relatives in predicting alcohol-related outcomes

BACKGROUND: The low level of response (LR) to alcohol is related to a family history (FH) of alcohol use disorders (AUDs), and each predicts alcohol-related outcomes. Few studies have evaluated the interrelationships between the number of alcoholic relatives, LR, and a range of alcohol-related outcomes. This study tests the hypotheses that there will be an inverse relationship between LR and FH and that LR will be a better predictor of the maximum quantity of alcohol consumed. METHODS: Data were extracted from personal interviews with 376 males from 20 years of follow-up in the San Diego Prospective Study. Level of response had been established at about age 20 through alcohol challenges in this population, about half of whom had at least one alcoholic relative. Face-to-face follow-ups with both the subjects and additional informants were carried out 10, 15, and 20 years later. These analyses used correlations and regressions to evaluate the relationship between the 2 major predictors (FH and LR) and 5 alcohol-related outcomes over 20 years of follow-up. RESULTS: As predicted, the alcohol challenge-based LR correlated significantly with the number of alcoholic relatives (up to -0.17 for subjects with clearly high and low LR scores). Each of the 2 predictors correlated with the 5 outcomes, including the maximum quantity of alcohol consumed since original testing, maximum frequency, nondiagnostic alcohol-related problems, the number of 11 DSM-IV (Fourth Diagnostic and Statistical Manual of Mental Disorders) abuse and dependence items, and having developed alcohol abuse or dependence. In hierarchical regression analyses, LR contributed significantly to the prediction of all 5 outcomes, even when considered in the context of FH, with only LR predicting drinking quantity and frequency, but both items adding to the prediction of alcohol-related problems and diagnoses. These results were not affected by the intensity of usual drinking when LR had been measured at age 20. CONCLUSIONS: Both FH and LR contributed to a range of alcohol-related outcomes, with LR alone significantly predicting maximum quantity and frequency in regression analyses.     

Endothelial dysfunction and high cardiovascular risk profile in severe alcoholics improve only partially following a medium-term alcohol withdrawal

Background: Little is known about brachial artery flow‐mediated vasodilatation (FMD) in active and medium‐term withdrawing heavy alcoholics (HA). Methods: FMD and some parameters of cardiovascular (CV) risk were measured in 29 HA (average alcohol intake 135, range 86 to 215 g per day) at baseline and after a 9 ± 7 months withdrawal and in 35 teetotalers. Results: HA showed baseline impaired maximal % FMD (8.5 ± 5.4 SD vs. 14.9 ± 7.4, <0.001 vs. teetotalers), higher systolic (SBP) and diastolic (DBP) blood pressure (+24 mm Hg, <0.001; +15 mm Hg, <0.01), uric acid (5.3 ± 1.1 vs. 4.4 ± 0.8 mg/dl, <0.05), high‐sensitivity C‐reactive protein (hs‐CRP; 2.7 ± 2.0 vs. 1.0 ± 0.9 mg/l, <0.02), endothelin‐1 (ET‐1, 0.88 ± 0.36 vs. 0.37 ± 0.10 pg/ml,<0.001), asymmetric dimethylarginine (ADMA, 0.50 ± 0.21 vs. 0.41 ± 0.12 μmol/l, p < 0.001), homeostasis model assessment of insulin resistance (HOMA‐IR) (2.3 ± 1.1 vs. 1.2 ± 0.4, <0.001), and urinary 8‐isoprostane (U8‐iso‐PGF2α) (237.2 ± 172.4 vs. 168.5 ± 96.6 pg/mg creatinine, <0.05). After withdrawal, SBP fell by 15 mm Hg, DBP by 11 mm Hg (p < 0.001), and hs‐CRP by 0.94 mg/l (p < 0.02), all remaining still higher than teetotalers (<0.05, 0.01, 0.05 respectively). ET‐1, HOMA‐IR, and U8‐iso‐PGF2α were unchanged (p = NS vs. baseline, <0.05 to 0.001 vs. teetotalers). Maximal % FMD rose (to 10.6 ± 6.2, p < 0.04), but it still remained impaired (<0.04 vs. teetotalers). ADMA increased further to 0.64 ± 0.15 μmol/l (<0.05 vs. baseline, <0.02 vs. teetotalers). Conclusions: HA show marked endothelial dysfunction (ED) and high BP, impaired insulin sensitivity, inflammation, increased oxidative stress, and elevated ET‐1 and ADMA, which are unaffected or only partially reversed by a medium‐term alcohol withdrawal. ED and related abnormalities persist in detoxified alcoholics, thus contributing to a greater CV morbidity and mortality.     

Biological and behavioral markers of alcohol sensitivity

This article summarizes a symposium that was organized by Dr. Kim Fromme and presented at the 2003 annual meeting of the Research Society on Alcoholism in Ft. Lauderdale, Florida. The four presentations illustrate the emerging technologies and methods that are now being used to investigate the genetic basis of differential sensitivity to alcohol and their behavioral manifestations. Combining human genotyping with laboratory measures of behavior and subjective reports, these presentations represent state-of-the-art approaches to crossing the bridge from the Decade of the Brain to the Decade of Behavior. Dr. De Wit's paper describes her research on the neurobiological basis for individual differences in sensitivity to the stimulant and sedative effects of alcohol. Evidence suggests that activity of the dopaminergic and GABAergic neurotransmitters underlie these stimulant and sedative effects, respectively. Both Drs. Hutchison's and Corbin's papers describe their research on polymorphisms for the serotonin transporter (SLC6A4) as a determinant of the subjective effects of alcohol challenge. Dr. Hutchinson's and Ms. Ray's findings indicate that individuals with the short form of the SLC6A4 alleles (S) demonstrated a low level of response to alcohol, thus supporting previous research that the S allele may be associated with increased risk for alcohol dependence. In contrast, Dr. Corbin did not find a reliable association between the SLC6A4 genotype and subjective response to alcohol. Mr. Cook's and Dr. Wall's paper adds another dimension to this article by presenting research on both the aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH2) genetic variants and their association with the alcohol-related flushing response that is prevalent in Asian populations. Dr. David Goldman provides concluding remarks.     

Thiamine status in liver and brain of rats genetically selected for different sensitivity to hypnotic effect of alcohol

BACKGROUND: The mechanisms of the different sensitivity or resistance of animals and humans to alcohol are still not completely understood. For further biochemical characterization of animals genetically selected for high-alcohol sensitivity (HAS) and low-alcohol sensitivity (LAS) with the hypnotic effect of alcohol, the thiamine status and thiamine metabolizing enzymes in these animals have been studied. METHODS: We investigated thiamine diphosphate and thiamine triphosphate levels as well as the activity of thiamine-dependent enzyme, transketolase, and thiamine-metabolizing enzymes, thiamine kinase, and thiamine triphosphatase in the liver and brain of HAS, LAS, and CAS (control) rats by standard biochemical techniques. RESULTS: It was found that the activity of transketolase, and the level of the coenzyme form of thiamine, thiamine diphosphate (TDP), were significantly lower in HAS versus LAS rats. The activation of transketolase by the exogenous TDP (TDP-effect) was significantly higher in the liver and brain regions of HAS rats compared with LAS rats. The level of TDP in the liver and cerebellum of HAS rats was significantly lower compared with LAS rats. These results indicate a severe deficiency of TDP in HAS rats. HAS rats have a significantly lower activity of thiamine triphosphatase, the additional source of TDP. Accordingly, HAS rats have much higher thiamine triphosphate levels in the liver and brain, compared with LAS rats. There were no significant differences between groups with respect to the thiamine diphosphatase and thiamine kinase activity. Most of the above parameters had the intermediate values in CAS rats, compared with LAS and HAS rats. These data indicate the possible role of the thiamine phosphate esters and related enzymes in the mechanisms that bring about the differential sensitivity to the hypnotic effect of alcohol. CONCLUSIONS: HAS rats have the genetically mediated thiamine diphosphate deficiency and increased thiamine triphosphate levels, probably due to reduced activity of thiamine triphosphatase in the liver and brain, compared with LAS rats. It can be related with the higher initial sensitivity of HAS rats to hypnotic effect of ethanol.     

Subjective responses to alcohol: a paradigm shift may be brewing

Background: The meta‐analysis by Quinn and Fromme (2011 ) is reviewed and integrated into the larger field. Guidelines for future research are presented. Results: With results of the meta‐analysis along with those of a recent comprehensive prospective study by our group ( King et al., 2011 ), there is a call to the field to specify terms and integrate theoretical frameworks to advance our knowledge and improve comparisons across trials. Conclusions: The meta‐analysis is both timely and thorough and will provide clinical researchers with important information to move the field forward.     

Effects of stress on alcohol consumption in rats selectively bred for high or low alcohol drinking

BACKGROUND: Stress has long been thought to influence the initiation and maintenance of alcohol drinking in humans. However, results of studies in animals suggest that the relationship between stress and alcohol drinking is not well understood. The purpose of this study was to examine the effect of unpredictable and uncontrollable restraint stress on alcohol consumption in two sets of rat lines selectively bred for alcohol preference (P) and high alcohol drinking (HAD1) and for alcohol nonpreference (NP) and low alcohol drinking (LAD1). METHODS: Male P (n = 26) and NP (n = 26) and HAD1 (n = 17) and LAD1 (n = 20) rats were counterbalanced on the basis of alcohol intake and assigned, in matched pairs, to either a stress (Stress) or a no-stress (Control) group. All rats were given a free choice between a 10% v/v alcohol solution and water, with food freely available. Unpredictable, uncontrollable stress, which consisted of immobilization in a nylon restraint sleeve for 30 to 120 min/day, was applied for 10 consecutive days. RESULTS: Stress moderately reduced alcohol intake in both P and HAD1 rats versus controls and had no effect on alcohol intake in either the NP or the LAD1 rats during the 10 days of stress application. Alcohol intake was increased for the first 5 days after stress termination in P rats but not in HAD1 rats. Alcohol intake remained stable for several weeks in both the NP and LAD1 lines after stress termination and then increased during the last 15 days of the 35-day poststress period in NP rats, but not in LAD1 rats. CONCLUSIONS: A reduction in alcohol intake during stress in rats with a genetic predisposition toward high alcohol intake seems to be a moderate but consistent finding, whereas an increase in alcohol intake after stress termination is less consistent and may be influenced by genetic background.     

A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans

BACKGROUND: Recent research has implicated the endogenous opioid system in the development of alcohol use disorders. The A118G polymorphism of the OPRM1 gene has been shown to confer functional differences to mu-opioid receptors, such that the G variant binds beta-endorphin three times more strongly than the A variant. The goal of this study was to test whether the A118G polymorphism is associated with sensitivity to the effects of alcohol. METHODS: Participants who were either homozygous for the A allele (n = 23) or heterozygous (n = 15) received intravenous doses of alcohol designed to reach three target levels of breath alcohol concentration: 0.02, 0.04, and 0.06. The testing procedure consisted of measures of subjective intoxication, stimulation, sedation, and mood states at baseline and at each of the three target breath alcohol concentrations. RESULTS: The results suggested that individuals with the G allele reported higher subjective feelings of intoxication, stimulation, sedation, and happiness across trials as compared with participants with the A allele. Furthermore, participants with the G allele were almost three times more likely to report a positive family history of alcohol use disorders than participants with the A allele. CONCLUSIONS: These findings may help to explain previous research suggesting that naltrexone is more effective among individuals with the G allele. A medication that reduces feelings of euphoria after alcohol consumption may be more successful among individuals with a genetic predisposition to greater feelings of euphoria after consuming alcohol.     

Reduced olfactory sensitivity,discrimination, and identification in patients with alcohol dependence

BACKGROUND: Various olfactory deficits have been reported in the alcohol-induced amnestic syndrome (Korsakoff's syndrome). Less is known about olfactory functioning in nonamnesic and nondemented alcoholic patients. METHODS: Olfactory performance of 30 alcohol-dependent patients was assessed unirhinally using the Sniffin' Sticks (threshold, discrimination, identification, composite TDI score) and compared with that of 30 healthy controls, matched for sex, age, and smoking status. RESULTS: Patients showed significantly reduced olfactory sensitivity (higher threshold), discrimination, and identification compared with controls. No group differences were observed in laterality. Identification and discrimination group differences remained significant after controlling for differences in sensitivity. Olfactory deficits in patients were present independent of age, gender, and duration of abstinence (<3 months) and were not attributable to smoking or general cognitive abilities. More than half of the patients (56.7%) could be classified as hyposmic. Lower overall olfactory functioning (TDI) was associated with longer duration of a regular alcohol intake and higher values of gamma-glutamyltransferase (GGT). CONCLUSIONS: Olfactory dysfunction is common in nonamnesic and nondemented patients with alcohol dependence. Results suggest a detrimental effect of alcohol on central olfactory processing.     

Effects of topiramate on urge to drink and the subjective effects of alcohol: a preliminary laboratory study

Background:  Topiramate was recently reported to be efficacious in reducing drinking rates and craving among individuals with alcohol dependence in a randomized controlled trial, but dose effects could not be determined. This laboratory study systematically examined the dose-dependent effects of topiramate on cue-elicited craving and other putative mechanisms of its pharmacotherapeutic effects on drinking.
Methods:  Male and female heavy drinkers ( n  = 61) were randomized to 1 of 3 medication conditions (200 mg/d; 300 mg/d; placebo) in a double-blind study. Participants reached the target dose after a 32-day titration period, then were stabilized for approximately 1 week. All then participated in a laboratory assessment of alcohol cue reactivity and of the subjective effects of a moderate dose of alcohol.
Results:  Both doses of topiramate reduced the frequency of heavy drinking during the titration period as compared to placebo. However, topiramate did not affect self-reported craving for alcohol during the titration period, during the cue reactivity protocol, or in response to the alcohol challenge procedure. Topiramate reduced the stimulating effects of alcohol ingestion compared to placebo, but only in the 200 mg group.
Conclusions:  The results of this study support previous findings that topiramate reduces drinking, but the behavioral mechanism underlying this effect does not appear to be attenuation of craving for alcohol as measured using the approaches employed in this study. Rather, the results tentatively suggest that topiramate may exert its beneficial effects by altering the subjective experiences of alcohol consumption. Limitations of the current study are discussed and complementary methods are recommended for future studies, such as the use of behavioral economic paradigms and ecological momentary assessment.     

P rats develop physical dependence on alcohol via voluntary drinking: changes in seizure thresholds, anxiety, and patterns of alcohol drinking

BACKGROUND: It has been proposed that the alcohol-preferring P rat meets many of the criteria for an animal model of alcoholism. However, the development of alcohol dependence has not been explored in rats that self-administer ethanol for less than 15-20 weeks. The present study investigated the development of physical dependence upon alcohol after 2-6 weeks of voluntary alcohol intake. Changes in bicuculline-induced seizure thresholds, microstructure of alcohol drinking, and anxiety-related behavior were used as indices of alcohol dependence. In addition, we evaluated the microstructure of alcohol drinking associated with the development of physical dependence upon alcohol. METHODS: Alcohol (10% ethanol solution) was measured in graduated drinking tubes with both alcohol and water available continuously. Microstructure of alcohol intake was monitored by a computerized drinkometer. Physical dependence upon alcohol was determined by measuring bicuculline-induced seizure thresholds after alcohol withdrawal. Anxiety-related behavior of P rats after alcohol withdrawal was determined by the social interaction and elevated plus maze tests. RESULTS: Initial alcohol intake in the alcohol-preferring P rat was relatively modest (3.9 +/- 0.4 g/kg/day). Four days of forced alcohol exposure (initiation) followed by 6 weeks of voluntary drinking resulted in an increase of alcohol intake to 5.5 +/- 0.2 g/kg/day. Ethanol self-administration for 6 weeks, but not for 2 or 4 weeks, produced a significant reduction (30%; p < 0.05) in bicuculline-induced seizure thresholds during alcohol withdrawal. Alterations in the microstructure of alcohol intake (i.e., 90% increase in the size of alcohol drinking bouts compared to the baseline [p < 0.001] with no change in bout frequency) were associated with the development of alcohol dependence. Termination of alcohol intake after 6 weeks of voluntary alcohol consumption resulted in increased anxiety according to both the social interaction and elevated plus maze tests. CONCLUSIONS: The results of this study indicate that 6 weeks of voluntary alcohol intake are sufficient for the development of physical dependence upon alcohol in the alcohol-preferring P rats as measured by susceptibility to bicuculline-induced seizures. This time is much shorter than the 15-20 weeks reported earlier. Development of physical dependence to alcohol was associated with an increase in daily alcohol intake (40% over the baseline), an increase in alcohol intake during each drinking bout (90% over the baseline), and elevated anxiety during alcohol withdrawal.     

A genome-wide search for genes that relate to a low level of response to alcohol

BACKGROUND: The low level of response (LR) to alcohol is genetically influenced in both humans and animals, and a low LR is a characteristic of offspring of alcoholics that has been reported to predict alcoholism 10 and 15 years later. The genes that contribute to a low LR have not yet been identified. METHODS: A 12-item questionnaire that measures LR, the Self Rating of the Effects of Alcohol (SRE) instrument, was filled out by 745 individuals from the Collaborative Study on the Genetics of Alcoholism (COGA) for whom genetic material was available. These subjects were genotyped by using 336 markers with an average heterozygosity of 0.74 and an average intermarker distance of 10.5 cM. Both quantitative and qualitative nonparametric, sib-pair analyses were carried out for the SRE measure related to early drinking experiences. RESULTS: Correlations of SRE scores across related individuals were significant and between 0.16 and 0.22 for most values, compared with nonsignificant correlations of 0.03 or less among unrelated individuals. Linkage analyses performed by using the FIRST 5 variables (first five times alcohol is consumed) identified four chromosomal regions with lod scores > or = 2.0 whose maximum was also near a marker. One of these chromosomal regions previously was linked to alcohol dependence in the COGA sample. CONCLUSIONS: These data document the familial nature of a low LR to alcohol as measured by the SRE and suggest several chromosomal regions that might contribute to the phenomenon.